Local Anesthetics

Question 1

study henderson-hasselback equation

Answer 1

slide 11 of local anesthetics

Question 2

What is the mechanism of action of local anesthetics

Answer 2

• interact with Na+ channels
• increase threshold for depolarization
• block conduction

(i.e. block voltage-gated Na+ channels)

Question 3

which subunits are present in the sodium channel schematic?

Answer 3

• 1 ALPHA SUBUNIT with 4 domains, each containing 6 membrane spanning subunits
• 2 BETA SUBUNITS

Question 4

What state does the LA have to be in to pass through the lipid bilayer, inter the cell?

Answer 4

un-ionized

Question 5

TRUE or FALSE: local anesthetics are weak acids

Answer 5

FALSE –> weak bases

Question 6

Local anesthetics are ‘use-dependent’. What does this mean?

Answer 6

• channel has to open to let the anesthetic (R3-NH+) in from the inside
• more active the nerve is, the more rapidly the block develops

Question 7

Does chirality matter? Why? Consider the different forms.

Answer 7

yes it matters, R(+) more cardiotoxic than S(-)

Question 8

Which local anesthetics have less cardiovascular effect than R(-) Bupivacaine due to effect at cardiac Na+ channels?

Answer 8

S(+) Bupivacaine, Ropivacaine

Question 9

Describe the lipid solubility of local anesthetics

Answer 9

greater molecular weight = higher lipid solubility = bind more readily to Na channels

Question 10

Describe the protein binding of local anesthetics

Answer 10

high lipid solubility = increased protein binding = longer duration of action

Question 11

TRUE or FALSE: potency of LAs decreases with increasing molecular weight and decreasing lipid solubility.

Answer 11

FALSE: potency of LAs INCREASES with INCREASEING MW and INCREASE lipid solubility

Question 12

Which protein do LAs bind to?

Answer 12

alpha1-acid glycoprotein, and albumin

Question 13

Hypoxia, hypercarbia, and acidemia all decrease protein binding. Why is this important to note when administering LAs?

Answer 13

decrease protein binding –> increased bioavailability –> increased risk of toxicity

Question 14

Children younger than 6 months have _____________ protein binding capacity. (less/more)

Answer 14

less

Question 15

What is pKa?

Answer 15

pH at which the ionized and un-ionized forms are present in equal amounts

Question 16

Describe the pKa of LAs

Answer 16

low pKa = more non-ionized drug = fast onset of action

Question 17

lidocaine has pKa = 7.8. bupivacaine has pKa = 8.. which drug has a faster onset?

Answer 17

lidocaine

Question 18

What do clinicians administer to speed up the onset of epidural anesthesia? why?

Answer 18

• bicarbonate
• increases pH; increases non-ionized proportion of drug (more basic)

Question 19

Why does low pH in damaged tissue reduce the effect of LA?

Answer 19

increased H+ shifts the equilibrium towards the cationic form, which cannot enter the membrane

Question 20

What does speed of onset of LAs depend on?

Answer 20

pKa and molecular weight

Question 21

What does potency of LAs depend on?

Answer 21

lipid solubility

Question 22

What does duration of LAs depend on?

Answer 22

protein binding, which is linked with lipid solubility

Question 23

Describe the potency, duration of action, onset time, and tendency for systemic toxicity of larger lipophilic (i.e. high lipid solubility) LAs.

Answer 23

• more potent
• increased duration of action
• longer onset time
• increased tendency for systemic toxicity

Question 24

What is the order of peak plasma concentration after a single dose?

Answer 24

intrapleural > intercostal > lumbar epidural > brachial plexus > subcutaneous

Question 25

What is absorption of LAs dependent on?

Answer 25

- site of administration - rate (pressure) - dose of injection - vaso-activity of injectate (addition of epinephrine)

Question 26

Why are vasoconstrictors (adrenaline) added to LAs?

Answer 26

1) limit systemic absorption 2) increase [LA] at site of action 3) counteract tendency for LA to cause vasodilation

Question 27

Does cocaine need to be administered with epinephrine?

Answer 27

NO

Question 28

Are ester or amide LAs more extensively protein bound?

Answer 28

amide LA's extensively protein bound

Question 29

TRUE or FALSE: alpha 1 acid glycoprotein binds LA with low affinity

Answer 29

FALSE: HIGH affinity

Question 30

TRUE or FALSE: albumin binds in greater quantity due to its greater abundance

Answer 30

TRUE

Question 31

What are ester LAs hydrolysed by? What are they hydrolysed to?

Answer 31

plasma cholinesterases --> para-aminobenzoic acid (PABA)

Question 32

Which metabolite of ester LAs is known to cause allergic reactions?

Answer 32

para-aminobenzoic acid (PABA)

Question 33

Where are amide LAs metabolized? How are they metabolized? Is it slower or faster than ester LA metabolism?

Answer 33

- liver - aromatic hydroxylation, amide hydrolysis, N-dealkylation - slower

Question 34

Do amide or ester LAs have a higher allergic potential?

Answer 34

ester LAs = high allergic potential (PABA)

Question 35

Based on fiber diameter, which nerve fibers have a higher susceptibility to LAs?

Answer 35

thin C- and Ad-fibers

Question 36

TRUE or FALSE: nerves that fire at a low frequency are more likely to block

Answer 36

FALSE: high frequency more likely to block

Question 37

Longer/broader AP durations make nerves more susceptible to LAs. Why? Which fibers have a broader AP duration?

Answer 37

- channels are in activated state longer --> more chance for LA to enter - slow-conducting C-fibers have broader AP duration

Question 38

What is used to treat LA toxicity?

Answer 38

intralipid rescue